The purpose of the study is to: (1) characterize the pattern of cellular immune response to herpes simplex virus (HSV) in man in relation to the clinical and virologic course of the disease, and (2) to ascertain the immunologic differences between patients with recurrent and those with nonrecurrent disease by (a) detailed comparison of the two groups and (b) longitudinal long-term study of the course of the disease following primary infection. The virologic studies will include sequential quantitative viral culture, lesional interferon titration, and typing of isolates. Serologic studies will include complement fixation titer for HSV, neutralization titer for HSV 1 and 2, blocking activity of serum in an assay of direct lymphocyte-mediated cytotoxicity against HSV-infected cells, and cytolytic antibody titer in antibody-dependent cellular cytotoxicity tests with HSV-infected cells. The tests of cellular immunity utilizing subjects' lymphocytes and monocytes will include HLA typing, lymphocyte proliferative responses to concanavalin A and HSV antigens, lymphocyte interferon production in response to concanavalin A and HSV antigen, natural cytotoxicity and direct T lymphocyte-mediated cytotoxicity assay against infected cells and an antibody-dependent cellular cytotoxicity assay. Suppressor activity for immune cytotoxicity and post-incubation augmentation will also be determined in these patients. In addition 9 clinical parameters will be recorded during each episode studied. Patient groups to be studied are: (1) patients with primary genital herpes infection prospectively for 18 months, (2) patients with frequent genital recurrences stratified by frequency, (3) seropositive patients with no history of herpetic lesions, and (4) seronegative controls. In vitro studies will be conducted to characterize the cell populations mediating the 3 types of cytotoxicity assayed, to elucidate the augmentation and suppression of cytotoxicity by cells and humoral factors and to determine the effect of prostaglandin inhibitors and antiviral drugs on cell-mediated cytotoxicities. The effects of virus-induced target cell Fc receptors and soluble viral Fc binding activity on the function of cytotoxic cell populations and on virus neutralization, mononuclear cell restriction of virus replication will be determined.